Liver failure accounts for a large number of deaths globally. One of the major treatment strategies for liver failure is liver transplantation, wherein a part of the donor organ is transplanted into the recipient. Although a successful form of treatment for liver failure, liver transplantation has a major limitation in the form of shortage of donors. To overcome this problem of limited donors, extracorporeal artificial liver assist devices have been developed that work on the principle of physical/chemical gradients and adsorption to remove the water soluble toxins in the blood/plasma. However, apart from detoxification, the liver is also largely involved in synthetic functions, such as, the synthesis of albumin. These synthetic functions are not replaced by the artificial liver assist devices in use clinically. Bio-artificial liver devices consist of a cell housing bioreactor that is able to replace most of the functions of the liver including metabolism and synthesis.
Many designs have been proposed for use as bio artificial liver device, including but not limited to the flat bed bioreactor and perfused bed bioreactor and the more widely accepted hollow fiber bioreactor. The hollow fiber bioreactor system allows for immune-isolation and protects the cells from shear stress, a major disadvantage with the other designs.
Typically the bioreactor system is connected externally to a plasma separator system that separates out the plasma that enters the bioreactor from blood circulated extracorporeally. Plasma passing through the bioreactor system is treated by the cells housed in it and returned to the patient. However, such systems lack efficiency and are also complicated in processing.
The existing bio artificial technology revolves around modifying the design of hollow fiber bioreactor design or modifying the cell types being used in the existing designs for bioartificial liver systems. In one of the patents filed (WO 1992007615A1), the inventors have modified the hollow fiber bioreactor system by inoculating hepatocytes into a hollow fiber in a solution that forms a highly porous gel that contracts, leaving an open channel within the hollow fiber. That is the gel matrix (made of collagen) contracts within the hollow fiber lumen to facilitate perfusion, while plasma/serum flows around the hollow fiber.
In U.S. Pat. No. 7,160,719B2, the inventors have designed a bioreactor comprising a selectively permeable baffler that separates the fluid treatment compartment from the cell compartment.
In yet another patent filed related to Bioartificial Liver (U.S. Pat. No. 5,605,835A), a bioreactor was designed to maintain animal cells in a functioning state over extended periods of time wherein a permeable membrane divides the interior into a cell chamber and a cell nutrient and waste chamber in which the cell chamber constitutes a biocompatible matrix entrapped with cells.
All these designs have tried to improve the functionality of the cells within the bioreactor system, by compartmentalizing the cells to prevent exposure to toxins. However each of these reactors needs to be connected to a separate plasma separation unit that separates out the plasma that will eventually flow through these reactor systems. This inevitably increases the overall volume of blood that is drawn out of the body resulting in stress on the body due to blood loss. Also, in all the designs mentioned above, the surface area available for the entrapped cells to grow is lesser as compared to the surface area provided by a cryogel system.
WO2016015371 relates to a bio-artificial liver system comprising plasma separation/blood transfusion cycle, a bioreactor cycle, and a cell renewing system. However, here in this system all the three parts are in communication through pipelines.
CN2638736 relates to a heterozygotic artificial liver support apparatus which includes an integrated control circuit, an input end, a plasma separation device, a plasma exchange device, a plasma absorption device, a biological response device, a plasma output device and an output end. Here also, all the components are connected through pipelines.
There exists a need for a hybrid bio artificial liver support system that integrates the components of the artificial liver and bio artificial liver assist device in a single unit including detoxifier, cell seeded bioreactor, plasma separator etc. and still capable of performing multiple hepatic functions efficiently.